INTRODUCTION

The International Classification of Epilepsies and Epileptic Syndromes (1) divides epilepsy, first, on the basis of whether the seizures are focal (localization-related epilepsies), generalized (originating at some point within and rapidly engaging in a bilaterally distributed network), or unknown (epileptic spasm). Next, epilepsy is divided by etiology (genetic, structural/metabolic, and unknown cause). Genetic epilepsy is defined as the direct result of a known or presumed genetic defect(s) in which seizures are the core symptom of the disorder. Structural/metabolic epilepsies require a distinct structural or metabolic condition or disease that has been demonstrated to be associated with a substantially increased risk of developing epilepsy in appropriately designed studies. Epilepsies of unknown cause are designated by an underlying cause that is as yet unknown.

Focal seizures are defined as originating within networks limited to one hemisphere, and for each seizure type, ictal onset is consistent. The distinction between the different types (ie, complex partial and simple partial) was eliminated in the ILAE 2010 seizure classification. However, it is important to recognize impairment of consciousness/awareness, other dyscognitive features, localization, and progression of ictal events in evaluating individual patients.

DEFINITIONS

A focal seizure without impairment of consciousness or awareness (corresponding to simple partial seizure in the previous classification) is one that arises from a localized area within one hemisphere without impairment of consciousness. A focal seizure with impairment of consciousness or awareness (corresponding to complex partial seizure in the previous classification) is a partial-onset seizure that is characterized by impaired consciousness, unresponsiveness, and automatic behavior often followed by postictal confusion. Impaired consciousness is defined as the inability to respond normally to exogenous stimuli by virtue of altered awareness or responsiveness (2). Awareness refers to the patient’s contact with events during the period in question and its recall (2), whereas responsiveness is the ability of the patient to carry out simple commands or willed movements.

ETIOLOGY

By definition, focal seizures imply the presence of a focal abnormality in one cerebral hemisphere. A definite etiologic factor can be identified by magnetic resonance imaging (MRI) in approximately 75% of patients with partial seizures (3–5). These include birth asphyxia, intrauterine infections (toxoplasmosis, cytomegalovirus, rubella, or syphilis), congenital anomalies, head trauma, meningitis, viral encephalitis, parasitic infections (cysticercosis and echinococcosis), neoplasms, arteriovenous malformations, cerebral embolization from congenital heart disease, or disorder affecting the intracranial vessels, as in fibromuscular dysplasia and moyamoya disease. Head injury and viral encephalitis have a predilection for the temporal lobe (6,7). Approximately 30% of patients who undergo surgical treatment for intractable focal seizures have a foreign tissue lesion detected on pathologic examination (8). Mesial temporal sclerosis (MTS) has been established as a causative factor in 50% to 60% of adolescents and adults with temporal lobe epilepsy (TLE) (9–11). Hippocampal pathology shows neuronal loss and gliosis in the Sommer sector, end folium, and dentate gyrus in 50% of cases (12). However, other etiologies predominate in children below the age of 12 years. Duchowny et al found that in their surgical series of 16 patients with TLE, only 2 had MTS, 7 had abnormalities of neuroblast migration, and 3 had ganglioglioma (13). The common tumors associated with intractable focal epilepsy include low-grade gliomas, gangliogliomas, and dysembryoplastic neuroepithelial tumor (DNET) (14,15). Neuronal migration disorders have been increasingly recognized as a cause of epilepsy. Focal cortical dysplasia (16–18), lissencephaly (19), band heterotopia (20), nodular heterotopia (21), the bilateral perisylvian syndrome (22,23), and schizencephaly (24) often present with seizures. In a study correlating pathology and MRI findings in children with intractable partial seizures, Kuzniecky et al (25) described the presence of cortical lesions in 23% of patients. Tuberous sclerosis, Sturge–Weber syndrome, neurofibromatosis, epidermal nevus syndrome, and hypomelanosis of Ito are neurocutaneous disorders associated with early-onset seizures (26). Coexistence of certain tumors such as ganglioglioma and DNET with cortical dysplasia, most frequently observed in the pediatric population, may suggest a hamartomatous nature of the neoplasms (27,28). The association of hippocampal sclerosis with cortical dysplasia remote from the mesial structures is well established in patients with TLE (29,30).

SEIZURE PHENOMENA

The symptomatology of focal seizures depends greatly on the location of the seizure focus within the cerebral cortex. Although a given symptom may occur with seizures arising from different locations, the combined information from seizure symptomatology and electroencephalogram (EEG) findings enables one to determine the location of seizure focus. Focal seizures with motor manifestations may result from ictal onset within or propagation to the precentral and postcentral gyri of the contralateral hemisphere or the supplementary motor area (31). The ictal symptomatology of epileptic seizures in general is a reflection of the activation of symptomatogenic zones. The activation is usually the result of spreading the epileptiform discharges from the epileptogenic zone to the adjacent cortex, which when activated produces the ictal semiology. Auras consist exclusively of subjective warning symptoms and usually occur at the beginning of a seizure. Depending on the methodology and selection of patients, auras have been reported by 20% to 90% of those with focal-onset seizures (32–34). Focal seizures with loss of awareness or consciousness arise from the temporal lobes in the majority of cases. However, in 15% to 20% of cases, an extratemporal focus in the mesial frontal, opercular insular region, cingulate gyrus, or orbitofrontal cortex is seen (35). Postictal dysfunction has localizing value but does not reliably identify the site of ictal onset. The International Classification of Epileptic Seizures provides a useful approach to understanding the symptomatology of focal seizures (2). This classification is electroclinical—in other words, based on both seizure semiology and EEG findings—whereas a recently proposed semiologic seizure classification by Lüders is independent of EEG or imaging findings (36). A list of common focal seizures and their anatomical associations follows.

Focal Seizures With Motor Signs

Focal seizures with motor signs are the most common form of what was previously termed “simple partial seizures” because of the prominent representation of the motor cortex and high epileptogenicity of the peri-rolandic cortex. These symptoms are contralateral (at least at onset) and usually consist of positive (irritative) symptoms, less often negative (inhibitory) symptoms, or a combination of the two.

Focal Motor Seizures With and Without March

Motor seizures can be clonic or tonic, involving any portion of the body, depending on the site of origin of the ictal discharge. The focal seizure may remain localized to one cortical region, or spread to contiguous cortical areas, producing a sequential involvement of body parts in an epileptic march. This pattern is often referred to as a Jacksonian march. Postictally, a temporary weakness, Todd’s paralysis, may be seen, especially if the seizure is severe or prolonged (7). Focal clonic seizures can occur with ictal discharges in any cortical region. The name epilepsia partialis continua (EPC) describes focal motor status epilepticus that is typically chronic.

Versive Seizures

Seizures beginning in or spreading to area 8, the frontal eye field, and the supplementary motor area, or the mesial part of premotor area 6, produce contralateral conjugate deviation of the eyes and turning of the head. When this movement is unquestionably forced and involuntary, the seizures are termed versive seizures and lateralize seizure onset to the contralateral hemisphere (37). Forced and sustained head and eye version, continuing through generalization or occurring within 10 seconds before generalization, was the best lateralizing sign, identifying a contralateral seizure focus in more than 90% of seizures (38).

Supplementary Sensorimotor Area Seizures

The supplementary sensorimotor area (SSMA) may be activated during seizures arising in patients with an epileptogenic zone in the posterior mesial or superior frontal area of one hemisphere. Seizures are frequent, brief, and usually out of sleep with abrupt bilateral asymmetric tonic posturing of the extremities. The posturing predominantly affects the proximal musculature with stiffening and gross flailing movements (15,16,39,40). Speech arrest and vocalization are common, but consciousness is often preserved. Ictal contraversive head and eye version may serve as a lateralizing feature if they precede secondary generalization. SSMA seizures may be confused with psychogenic seizures and parasomnias such as night terrors or confusional arousals.

Aphasic Seizures

Ictal language disturbances during epileptic seizures include speech arrest, aphasia, or vocalization. Seizures that begin with aphasic speech arrest, without altered consciousness, are generally considered to originate in the dominant posterolateral temporal region (41,42). Lüders and coworkers (43) demonstrated the presence of a basal temporal language area (BTLA) by electrical stimulation with subdural electrodes (43,44). Speech arrest has been demonstrated in seizures originating in the dominant BTLA (45,46). Seizures arising in the frontal operculum of the dominant hemisphere can give rise to epileptic aphasia (47). Vocalizations, sounds of no speech quality, may be seen with simple partial seizures affecting the suprasylvian area of the frontal lobe as well as complex partial seizures. They have no lateralizing value (48). Following the end of a focal seizure with or without loss of awareness, postictal aphasia may be detected by asking the patient to name items or read, and is 80% to 90% reliable in lateralizing seizure onset to the language-dominant hemisphere (49,50).

Focal Seizures With Somatosensory or Special Sensory Signs

Sensory or motor phenomena are often the initial symptoms of seizures starting in or near the postcentral area. Sensory phenomena include tingling, numbness, or paresthesias contralateral to the epileptogenic focus. The sensory phenomena may march to adjacent sensory or motor areas. The frequency of motor phenomena is due to intimate connections between the sensory and motor areas (6), as shown by motor phenomena observed in 25% of cases during electrical stimulation of the postcentral gyrus. Sensory symptoms that are ipsilateral or bilateral in distribution and identical to those occurring only contralaterally are believed to originate in the secondary sensory area at the base of the motor strip in the frontoparietal operculum (51). Rolandic epilepsy often manifests with focal motor seizures with preserved consciousness or as focal onset with secondarily generalized tonic–clonic seizures. They usually involve the face, oropharyngeal muscles, or arm on one side, and, less commonly, the leg. Sometimes they are associated with sensory phenomena such as tingling or numbness.

Visual seizures are focal seizures involving the visual cortex in the region of the calcarine fissure. They usually consist of flashes of light or colors in the contralateral hemifield with preserved awareness or consciousness. Visual seizures should be distinguished from migraine, which usually produces negative phenomena such as scotomas or hemianopsia. More elaborate visual phenomena (ie, formed visual hallucinations) are seen with seizures starting in the posterior temporal regions. Seizures starting from the occipital cortex may spread to the temporal lobes, producing impairment in awareness or consciousness (52).

Auditory seizures are seen at onset from the auditory cortex in the superior temporal gyrus. They usually manifest with sound such as humming, buzzing, roaring, or whistling. More elaborate hallucinations (music, voices, etc.) result from involvement of the associated auditory areas (6).

Olfactory and gustatory seizures present with an aura of an unpleasant odor or a bad taste in the mouth. They are usually observed with seizures arising from the anterior temporal lobe or insular region.

Vertiginous phenomena are sometimes reported by patients as the aura preceding their loss of awareness or consciousness. This may be a light-headed feeling or actual vertigo. Vertiginous phenomena are encountered with focal seizures of posterior temporal lobe onset (53,54).

Focal Seizures With Autonomic Symptoms or Signs

Autonomic symptoms in the form of flushing, pallor, sweating, pupillary dilation, nausea, vomiting, borborygmi, piloerection, or epigastric sensations are often seen in CPS, especially those starting in the anterior temporal lobe, opercular–insular region, and orbitofrontal cortex (54–56). Ictal gastrointestinal symptoms that are limited to visceral sensations are more common in children; they include painful cramping, periumbilical pain, bloating, nausea, vomiting, and diarrhea. Pallor and cold sweating may accompany the abdominal symptoms in children and may be misdiagnosed as psychogenic pain (57). Sinus tachycardia, the most frequent cardiac concomitant of seizures, has been reported in several case studies (58,59). Sinus bradycardia, sinus arrest, atrioventricular block, and prolonged asystole occur much less frequently. Sudden unexplained death has been postulated to be a result of autonomically mediated fatal cardiac arrhythmia or sudden “neurogenic” pulmonary edema associated with seizures (60–62).

Focal Seizures With Psychic Symptoms

Focal seizures with psychic symptoms refer to alterations of higher cerebral function—dysphasia, dysamnesia (déjà vu or jamais vu), affective behavior (fear, anger), cognition (distortion of time sense, dreamy states), illusions (micropsia or macropsia), or hallucinations (voices, music, or scenes). They are usually followed by a loss of awareness or consciousness phase; only rarely do they occur in isolation.

As mentioned previously, focal seizures may evolve to secondarily generalized tonic–clonic seizures directly, or after a loss of awareness or consciousness phase (2). The ictal discharge may spread from the focus to contiguous areas or to distant regions by way of specific pathways or callosal fibers connecting homologous areas of the cortex in the opposite hemisphere.

Focal Seizures With Loss of Awareness or Consciousness

Approximately 50% of patients with focal seizures with loss of awareness or consciousness report a warning symptom or aura. An aura is, by definition, a simple partial seizure. It may take different forms depending on the location of the seizure focus, as described previously. Focal seizures of mesial temporal onset are most commonly preceded by a rising epigastric sensation. Young children sometimes run to their mother and cling to her fearfully (61). The aura is more clearly expressed as the child gets older. The aura is followed by partial or complete loss of consciousness, unresponsiveness often with a vacant stare, behavioral arrest, and some stiffening of the body. Duchowny et al (62) noted that focal seizures in infants under 2 years of age frequently consisted of behavioral arrest with tonic upper extremity extensor stiffening. Automatisms defined as more or less coordinated, involuntary movements occurring during a period of altered awareness are frequently seen in focal seizures. These invariably take place during the ictus, less commonly in the postictal period. They may consist of stereotyped movements of the mouth and lips, oroalimentary automatisms such as lip smacking or swallowing, fumbling or grasping movements of the hands, blinking, grimacing, bicycling movements of the legs, walking or running about, laughing, crying, or complex motor activity. Automatisms tend to be simpler in the younger children, whereas highly organized behavioral sequences and complex gestural automatisms are observed in the older children and adults (62–64). The motor phenomena in preschool children may consist of symmetric tonic or clonic movements of the limbs and atonic phenomenon such as head nodding resembling infantile spasm or hyper-motor turning movements and postures similar to frontal lobe seizures in adults. Unilateral dystonic posturing is more often seen in focal seizures of temporal lobe origin and has good lateralizing value (65,66). Posturing in frontal lobe seizures tends to be more often tonic and bilaterally asymmetric. Temporal lobe seizures usually last 60 to 90 seconds and are followed by a postictal period lasting several minutes to hours (67). The child is often lethargic during the postictal period and may complain of headache. Postictal dysphasia may also be seen. The patient is usually confused postictally and may engage in automatic behavior. Attempts to restrain the patient may result in aggressive behavior, which is usually nondirected (68). One-third to one-half of patients with focal seizures may go on to have a secondarily generalized tonic–clonic seizure, more often out of sleep.

Frontal Lobe Seizures

Frontal lobe seizures (69–73) can usually be distinguished from focal seizures arising from the temporal lobes and other regions (Table 33.1). These seizures often have a bizarre clinical presentation, have minimal or absent interictal and ictal EEG abnormalities, and are sometimes mistaken for psychogenic seizures. Frontal lobe seizures represent the largest subgroup of extratemporal epilepsy, accounting for 30% of focal epilepsy (74,75). The semiology of frontal lobe seizures differs according to the location of the ictal onset zone and its propagation pattern (Table 33.2). In practice, large epileptogenic zones, the high speed and pattern of seizure propagation, and extensive overlap among different types can make subclassification difficult without invasive EEG recordings.

RASMUSSEN SYNDROME

Rasmussen syndrome (RS) is characterized by intractable focal motor seizures, declining cognitive function, progressive hemiparesis, visual field abnormality, and contralateral focal, predominantly perisylvian cortical atrophy. Changes in signal intensity may also be seen in the deep gray and white matter. The onset of the disease occurs at 10 years or younger in 85% of patients (76). Epilepsia partialis continua or focal motor status occurs in one half of patients at some point in their course (77). The etiology is not known, but an autoimmune process is important in the pathogenesis of RS, and it is believed that the glutamate receptor subunit, GluR3, may be an important autoantigen (78–80). Neuropathology characteristically shows perivascular lymphocytic cuffing and proliferation of microglial nodules in the cortex of the affected hemisphere (81–83). In-situ hybridization techniques were reported to show most Rasmussen patients to have neurons with cytomegalic inclusion virus (84); others, however, have not confirmed this. T-cell mediated cytotoxicity may also play a role (85). Following cleavage of the GluR3 protein by Granzyme B, the immunogenic section of the GluR3 protein becomes exposed to the immune system (86).

The EEG may show background slowing, disruption of sleep architecture, and frequent epileptiform discharges over the affected hemisphere. With progression of the disease, the spikes may become bilaterally synchronous and appear in the contralateral hemisphere (87–89). Computed tomography (CT) and MRI scans may show diffuse atrophy of the involved hemisphere (90). Proton MR-spectroscopy may reveal decreased N-acetylaspartate (NAA) concentration in patients with RS (91). These findings correlate well with brain atrophy and neuronal loss. For reasons that are not yet clear, Rasmussen encephalitis is essentially a unilateral disease.

TABLE 33.1

Rasmussen syndrome is notoriously difficult to treat and does not show the same dramatic response to IV medications as do other forms of status. IV immunoglobulin, high-dose steroids, or both, may produce some reduction of seizure frequency in the short term in a few cases (92), but surgical removal of the affected hemisphere is the standard therapy (93). A trial of Tacrolimus was found to slow the rate of neurologic deterioration, but it did not improve seizure frequency (94).

In the John Hopkins experience, 88% of children who underwent hemispherectomy became seizure free or have occasional, nondisabling seizures (93,95,96). Early hemispherectomy, although increasing the hemiparesis, reduces the overall burden of the illness because of a marked decrease in both frequency and severity of seizures. Because hemiplegia is inevitable with or without surgery, early surgery may allow the child to return to a more normal life by preventing the cognitive decline that is the result of constant seizures.

DIFFERENTIAL DIAGNOSIS

Pseudoseizures are in the differential diagnosis of any seizures, especially if presenting with bizarre and unusual patterns or prolonged generalized seizures with intact memory of the event. There is usually no postictal confusion. Pseudoseizures often can be terminated abruptly with suggestion (97,98). The frequency of pseudoseizures may be unrelated to antiepileptic drug (AED) levels. Video-EEG monitoring reveals no seizure pattern during the episode. Psychogenic unresponsiveness (that is, unresponsiveness during the presence of a preserved alpha background rhythm) is also very helpful. Pseudoseizures occasionally coexist with true seizures, and the monitoring must document all the seizure types reported by the family. Migrainous phenomena (97) may be difficult to distinguish from focal seizures, especially if they are associated with visual hallucinations or confusions. Migraine and partial seizures may coexist, or at times migraine may be followed by a partial seizure. The prodrome of the migraine attack usually develops more slowly than the epileptic aura. The frequent occurrence of vomiting and family history makes this diagnosis more likely. The recording of a typical episode in the laboratory with EEG and video monitoring is helpful.

TABLE 33.2

Radiologic Findings

MRI is the imaging modality of choice in a child with suspected focal structural epilepsy because of its inherent advantages in soft tissue contrast, spatial resolution, multiplanar capabilities, and lack of bone artifact. Kuzniecky et al correlated the MRI imaging results with pathology in 44 children with intractable epilepsy and showed a potential epileptogenic abnormality in 86% of patients (98). CT scanning is inferior in detecting lesions that may be seen only on MRI, with the exception of revealing intracranial calcification in Sturge–Weber syndrome and congenital brain infections such as toxoplasmosis or cytomegalovirus. MRI reliably demonstrates hippocampal atrophy in 70% to 90% of patients with mesial TLE (99,100). Accurate assessment of hippocampal size by volumetric studies has been shown to correlate with severity of neuronal loss in the hippocampus (101) and seizure outcome following resection (102). MRI has led to increased recognition, better characterization, and improved understanding of malformations of cortical development (MCD). The generalized MCDs include lissencephaly, pachygyria, band or laminar heterotopia, and subependymal heterotopias. Localized forms of MCDs include focal cortical dysplasia, polymicrogyria, focal subependymal heterotopias, and schizencephaly (103,104). The identification of a focal MCD and complete removal of the lesion is followed by good seizure control in 77% of patients (105). MRI is very sensitive in detection of tumors; vascular malformations such as cavernous hemangiomas, arteriovenous malformations, and subependymal nodules; and cortical tubers in tuberous sclerosis. Positron emission tomography (PET) scans may show an area of hypometabolism interictally and a focus of hypermetabolism on ictal scans (89,90). Unilateral temporal lobe hypometabolism is present in 70% to 80% of patients with TLE (106), and corresponds pathologically and anatomically to the depth electrode localization of the epileptic zone (107). Focal cortical dysplasia (FCD) may be difficult to visualize in very young children because of incomplete myelination. Interictal PET is useful in demonstrating areas of hypermetabolism corresponding to FCD in infants and children with catastrophic epilepsy. In the early stages of Rasmussen encephalitis, the MRI may be normal, but the PET scan may show focal or diffuse hemispheric hypometabolism. Flumazenil PET reveals a reduction in benzodiazepine receptor binding in the epileptic focus of partial epilepsy (108). Carfentanil PET studies of TLE have revealed increased mu-opiate receptor binding in the neocortex of the epileptogenic temporal lobe, correlating directly with a decrease of glucose metabolism seen on FDG-PET (109). Single-photon emission computed tomography (SPECT) has been used in patients with refractory seizures considered for epilepsy surgery. Interictal SPECT demonstrates hypoperfusion in 40% to 70% of patients with focal epilepsy (110). Ictal SPECT has been reported to have localization accuracy of 70% to 100% in TLE (111) and up to 90% in selected patients with frontal lobe epilepsy (112,113).

Interictal EEG

The interictal EEG may be normal in 30% to 40% of patients with clinically documented focal seizures. A normal EEG, however, does not rule out the diagnosis of epilepsy. The chance of finding an abnormality is increased by performing repeated or prolonged EEGs, sleep recordings, additional closely spaced electrodes, appropriate montages, and hyperventilation. With these techniques, the yield may be increased up to 90% (114–116). A unilateral temporal lobe focus is found in most cases of focal epilepsy. Bitemporal sharp wave foci are seen in 25% to 33% of patients (107). An extratemporal focus is seen in 15% to 20% of patients, usually in the frontal lobe (13). Focal intermittent rhythmic slowing may be seen intermittently in approximately half the patients with focal seizures (114–117) and has the same significance as focal spikes. One may also find focal slowing that is nonrhythmic with suppression of the normal background rhythms in 75% of patients (114). It is important to exclude nonepileptiform sharp transients such as small sharp spikes, psychomotor variants, or 14- and 6-Hz spikes. In addition, benign focal epileptiform discharges of childhood may occur in asymptomatic children (118). These are usually found in the central or midtemporal location, have a characteristic stereotyped waveform, and are markedly activated during sleep.

Ictal EEG

According to Gastaut (119), the ictal EEG is abnormal in more than 95% of cases. In 75% of patients, the interictal spikes or sharp waves show an abrupt cessation or decrease just before the ictal onset. This is then followed by rhythmic activity that shows a progressive buildup of amplitude and frequency (most often in the 13- to 30-Hz range, but possibly in the theta or delta range). This may be well localized to the area of focus, or it may be more widespread over that hemisphere (114). Focal beta activity at seizure onset seen in scalp recordings occurs in 25% of patients with FLE and is felt to be predictive of a good outcome after focal resection (120). Postictally, one may find slowing or flattening, which, if focal, may be helpful in lateralization (121). Sometimes, it is difficult to localize or lateralize the seizure onset from scalp recordings. Invasive recordings with subdural or depth electrodes may be indicated in such cases (121–127).

PROGNOSIS

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